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Oxidative Stress

Mechanisms of cell death are usually classified into two pathways, apoptosis and oncosis/necrosis. Necrosis/oncosis typically occurs in response to toxic injury, including that induced by chemical exposure and reactive oxygen species (ROS). In contrast to apoptosis, oncosis is characterized by cell and organelle swelling that eventually leads to the loss of plasma membrane integrity. The generation of ROS has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions. Delineating the processes that lead to ROS-induced necrotic cell death has profound clinical implications. For example, in many clinical situations in which ROS are implicated, including inflammation, diabetic pancreatic damage, ischemia/reperfusion injury, NMDA-receptor activated neurotoxicity, vascular stroke, and myocardial infarction, the predominant mechanism of cell death appears to be necrotic.

RFG 3 has identified a series of unique characteristics in biological molecules (pharmacophores) as inducers of the Nrf2/Keap1 system, which is one of the major cellular defense mechanisms against oxidative stress.

Trans-cinnamic aldehyde was shown to impair melanoma (malignant skin cancer) cell proliferation and tumor growth in skin and was also shown to induce an oxidative stress response in skin cells.

This data is significant because redox dysregulation is unique to cancer cells. These cancer cells can be targeted by pro-oxidant redox intervention using electrophilic dietary Michael acceptors. This can be a stepping stone towards finding more efficient treatment for skin cancer patients.

UVB light has been known to promote survival of potential cancer cells in the epidermis (skin) by activating a known extracellular signaling pathway known as PI3K. Quercetin (a dietary flavanoid) is a known inhibitor of PI3K, but degrades rapidly in the presence of ascorbic acid (a form of Vitamin C and present in many foods).

RFG 3 has found that although redox cycling of quercetin occurs even in the presence of ascorbic acid, stabilization reduces the accumulation of reactive quercetin products which eventually lead to cell death. This reduces the ability of the compound to induce cell death in UVB exposed skin cells

Key Research Highlights

Reactive oxygen species are a category of free radicals derived from molecular oxygen and has been known to cause oxidative stress in cells. These reactive oxygen species (ROS) are the subject of many research endeavors due to its ability to initiate some human diseases and toxicities. Members of RFG 3 investigate the molecular mechanisms by which ROS produce adverse health effects such as cancer.

The Southwest Environmental Health Sciences Center (P30 ES006694) is a Unit of the Center for Toxicology, at the College of Pharmacy, funded by the National Institute of Environmental Health Sciences. We also acknowledge the people – past, present, and future – of the Tohono O'odham Nation, on whose traditional lands we study and work.